Chemokine stromal cell-derived factor-1 induction by C/EBP activation is associated with all-trans-retinoic acid-induced leukemic cell differentiation

Stromal cell-derived factor-1 (SDF-1/ CXCL12) is one of the essential chemokines, which mediates hematopoietic differentiations. However, the mechanism by which SDF-1 expression is regulated in granulocyte differentiation is poorly understood. Here, we suggest a novel mechanism by which all-trans-retinoic acid (ATRA) induces the expression of SDF-1 during the differentiation of promyelomonocytic leukemic U937 cells. Moreover, we also demonstrate that activation of transcription factor C/EBP by ATRA regulates SDF-1 expression in U937 cells. In addition, we show that the cyclin-dependent kinase inhibitors p21 and Pyk2 are up-regulated by SDF-1 and increased markedly by the costimulation of ATRA and SDF-1. Furthermore, ATRA and SDF-1 additively induce U937 cell differentiation. Indeed, silencing the expression of SDF-1 inhibits ATRAinduced granulocyte differentiation significantly. Taken together, these results indicate that SDF-1 is involved in granulocyte differentiation in response to ATRA, mediated by the activation of the transcription factor C/EBP . J. Leukoc. Biol. 82: 000–000; 2007.